Steroids having a 17-positioned semicyclic double bond



xidation Oxidation e AcO CH: CH3

It has been found that, e. g. starting from secondary pregnane-20-ols and pregnene-20-ols which contain in 21-position a substituted methylidene group 17-ketones and A17-pregnene- 21-als can be obtained by suitably choosing the oxidation method. The course of the oxidation is especially inuenced by substituents in ring C, primarily by an esteried hydroxyl group in 12- position. 12-hydroxy compounds which are esteried in lz-position by a lower organic acid, e. g. acetic acid, under certain conditions of oxidation, yield mainly 17ketones, whereas those lz-hydroxy compounds which are esteried in 12-position by a higher organic acid, especially toluene sulfonic acid, give a good yield of A17- pregnene-Zl-als. For the oxidation, use may be made for example vof compounds of hexavalent chromium, such as chromic acid or chromyl chloride, and also permanganates, ozonization and the splitting of the ozonides, the action of peroxides, such as benzo-peracid, phthalic mono-peracd or hydrogen peroxide, advantageously in the presence of osmium tetroxide, and the splitting of the glycols produced by the hydrolysis of the oxide ring or by the direct attachment of two hydroxyl groups to the double bond in each oase, for example by means of chromic acid, lead tetraacetate or periodic acid.

If double bonds are present in the steroid nucleus, these are suitably protected from oxidation in known manner for example by means of halogen or hydrogen halide in cases where such protection is not rendered superfluous by the particular properties of the unsaturated system, as for example in the case of a double bond with keto group in a-position or a double bond in 11,12-position. Moreover' oxidizable substituents such as hydroxyl groups can be protected in known manner for example by esterifcation or etherication and after the oxidation, partially or wholly again liberated, as desired, for example by the action of hydrolyzing agents. If however a conversion is desired of free ring carbinol to keto groups, this can be carried out in known manner at the same time as the oxidation in the side chain or in a separate reaction, in particular under the influence of oxidizing or dehydrogenatingagents.

The following examples illustrate the invention, the parts being by weight unless otherwise stated and the relationship of parts by weight and parts by volume` being the same as that of the kilogram to the liter:

Example 1 6.8 parts of crude 3a,12a,20trihydroxy21 benzylidene-pregnane are dissolved in 200 parts by volume of glacial acetic acid and the whole boiled for 6 hours under reux. The acetic acid is thereupon distilled oi in vacuum and the residue taken up in methylene chloride. The solution after washing with water, 2 per cent sodium bicarbonate solution and water is dried over sodium sulfate and the filtrate concentrated by evaporation. The A1'I-3a-acetoxy-12a-hydroxy- 21-benzylidene-pregnene of the formula ACO- crystallizes from ether in colorless prisms which melt at 22o-223 C. [a]D21=-}-78 (c=1.044 in chloroform) In strictly analogous manner, other secondary 20-ols with a substituted methylidene group in 21 position can be converted into the corresponding steroids having a semi-cyclic double bond in l7position. Thus 3a,12a,20-trihydroxy-Zl-furfurylidene-pregnane yields A1l3aacetoxy12a hydroxy-2 1 -f urf urylidene-pregnene.

For the splitting oi of the Water, instead of glacial acetic acid, also formic acid or propionic acid can be used, while otherwise proceeding as above.

In this way All-Sa-formyloxyand A17-3apropionyloxy 12a hydroxy 21 benzylidenepregnene and A17-3a-formyloxyand A17-3apropionyloxy 12a hydroxy 21 furfurylidenepregnene are obtained.

The 21-benzylidene-pregnane-20-01 employed above is prepared for example as follows:

8.12 parts of 3a,12a-diacetoxy-20-keto-2lbenzylidene-pregnane and 24.5 parts of aluminum isopropylate are dissolved in 360 parts by volume of anhydrous isopropanol and the mixture subjected to a slow distillation during 12 hours for removal of the acetone produced in the reduction. The reaction mixture which is nally concentrated to about parts by volume is allowed to cool, treated with 800 parts by volume of molar Rochelle salt solution and the separated triol taken up in methylene chloride. It is Washed with water, dried and evaporated. The crude 21-benzylidene-20-ol thus obtained is suitably subjected to splitting out of water and simultaneous partial acetylation prior to purification.

From ethyl acetate the pure 3a,12a,20trihy' droxy-2l-benzylidene-pregnane crystallizes in colorless small needles which melt at 14S-150 C. By heating for 2 hours with acetic anhydride in the presence of pyridine on the water bath there is obtained from the triol a triacetate which melts at 18S-187 C. [alD23=-|47 (c=0.776 in dioxane).

Example 2 A solution of 4.07 parts of A5-3,20dihydroxy- 21-benzylidene-pregnene in 80 parts by volume of glacial acetic acid is boiled for 6 hours under reflux. The Working up takes place according to the method described in Example 1. By recrystallization from ether there is obtained the as starting material is prepared for ve'iaiiifple' 'as @Salce one' :Aooe

in colorless small plates- (With decomposition). in chloroform) lv- A e The compound gives "-1z4-dihydroxynaphthalene the -Raudnitz andP-uluj reaction-charac- -teristicof aldehydes. l i l e,

This compoundis obtainedastill betterfy'eld by carrying out the :oxidation as follows: Y.

'I'hrougl-l-.v two dropplngefunnels there are simule taneously added fin the course -ofQ r.liours with exclusion of oxygen and moisture, 500 @parts VolumeofeasO/Lfmolar ,solutionof AlN-teufacetolll-yjg 12otosyloxye2l -benzvy-lidene pregnene and 115 parts by yol-umeofa '-018 molar anhydrousethereel solution lof )hydrogen peroxide to va stirredmixf ture of 5) parts of Vanhydrous sodium'sulfatel-O part of asm-'lum tetroxfl-de and y20m-parts by volume of Ydry ether.' In 'order to Ycomplete the oxidation; the :reaction `:mixture vis, stirred lfor -alzlot'her-*Z hourslat room-temperature, and thendill-,lted with 11000 parts :by vvolumebfether and for the removal of the osmiurn {agi-tailed -for 24 hours with a zsolu tion et 6` :parte ofv Vsed-lum sulte Iin 5500 parts, by volume of Water. The aqueous layer is then removed and extracted three times with 500 parts by volume of ether on each occasion, and the combined ethereal solutions are washed in turn with Water, 2% sod'ium bicarbonate solution, and Water, then dried with sodium sulfate, and ltered and the ether distilledoi. The residue is dissolved in 50 parts by volume of anhydrous pyridine and 30 partsby volunie of acetic :anhy dride and the mixture` allowed `t`o stand at room temperature under moisture seal. .n V

After" 16 Hours the' eics's ofiyf'e ad 'c'tc anhydride andthe 'aeetic A dV that "has fojd are distilled on under reuoeeu' pressure at not more than 25 C. The residue vis taken-'iii ether andthe' 'sc'llltin Washed '.cr'isctillywlth 1li-hydrochloric "acid, Water,l `2`% sdi'x' b'itaiborlete solution, and water, alle@ with sodiuin sulfate, lterei, and evaporated.. l"Il'ie crude product smells strongly o'f be'ialdehyd. By @crystallization from a mixture' of' trier ed petroleum ether' it yields .All-{e-acetoky-l'a toeyloxy-pfegnee-al-alj of P1 "i'504'151' "C1 `I't has the form-ula 1.5 parts of AlI-Seeacetoxy l12ulhydroxy-21 benzylidene-pregnene and 3.0 parts of p-toluenesulfo-chloride are allovve'cl to stand at about 30 C. in 10 parts by volume of pyridine for 6 days with exclusion of m'oisture. The solution is then treated at 0 C. carefully with 3. parts by volume of water, the tosylate, precipitated by further addition of Water, taken upein ther and washed consecutively with 0.5N-hydrochloric acid, water, -.N-sodium bicarbonate. and waterlV 'The dri'd ether solution is evaporatedfandthefcruderoduct erystallizedf-rozri 95' .per ent fethafnh By vreerystaslliiati'on'from hexane,-tl'rol'laeactoxyi 12aetos`yloxy=2lbenzylideneepregnerleuis-fobteied as colorless- .hat nprisms of double -rltlngf 1:012104? C."a`1d-1-25'-12`6 G. (Wth-'dGOYID!GI)'-; l'al'llii? Vtcl' in chlb'fhif 'l ce i Example 4 2.7 parts of A173a,12adiacetoxy2l-benzylidene-pregnene are dissolved in 1500 parts by volume of anhydrous ethyl acetate, the whole cooled to 25 C. and 6.5 mol-equivalents of ozone passed in. The excess of ozone is blown oi with nitrogen shortly after the completion of the introduction and the solution, after addition of 200 parts by volume of glacial acetic acid. and 57 parts of zinc dust, stirred for 1 hour at room temperature. The zin-c dust is then ltered off and the liquid evaporated in vacuum. The residue is taken up in ether, the solution washed with 2 per cent sodium carbonate solution and water, dried and evaporated. 'I'he crude neutral substance is chromatographed on 60 parts of aluminum oxide. With pure hexane only low molecular splitting products are dissolved out. A hexane-benzene mixture (1:1) eluates the 3a,12a-diacetoxy-aetiocholane-17one of the formula l CH:

which is recrystallized from ether-petroleum ether. Colorless prisms are obtained which melt at 152-153 C. [alD22=|+180 (c=1.055 in acetone).

The A17-3a,12adiacetoxy2l-benzylidene-pregnene employed as starting material is for eX- ample prepared as follows:

2.8 parts of A3aacetoxy12a-hydroxy-21- benzylidene-pregnene are heated to 95-1003 C. for 21/2 hours in a nitrogen atmosphere with 50 parts by volume of pyridine and 20 parts by volume of acetic anhydride. The reaction mixture is thereupon evaporated in vacuum and the residue taken up in either. The ethereal solution is washed consecutively with 0.5N-hydrochloric acid, water, 0.5N-sodium bicarbonate and water, dried and evaporated. The A17-3a,12q.-di acetoxy 21 benzylidene-pregnene crystallizes from ether-isopropyl ether in colorless small needles. On introduction into a block preheated to 162 C. the substance melts, and may afterwards solidify again completely and then melts iinally at 164-167 C. [alD21=-}100 (c=1.049 in chloroform).

Example The A5173;-acetoxy2l-benzylidene-pregnadiene, obtained according to Example 2 may be oxidized to A4-androstene-3-17-dione:

om g o of chromium trioxide is carefully destroyed with sulphurous acid. The A-androstene-l'l-dione is isolated from the neutral oxidation product by chromatography on 50 parts of aluminum oxide. The substance eluated -with hexanebenzene mixture (1:1), after recrystallization from etherpetroleum ether melts at 169-171 C. and exhibits a specic rotation laln24=l+198 (c=1.120 in chloroform). In a mixed melting point test it proves to be identical with the substance known to be A4-a-ndrostene-3,l'l-dione.

The A1117 3 keto-21-benzylidene-pregnadiene employed as starting material is obtained from A511'I 36 acetoxy-Zl-benzylidene-pregnadiene in the following manner:

A supsension of 2.15 parts ofA517-3acetoxy 21-benzylidene-pregnadiene in 110 parts by volume of methanol is, after addition of 1.40 parts of potassium carbonate in 14 parts 'by volume of water, heated to boiling for 2 hours. After cooling the whole is filtered with suction, washed with methanol and water and dried. There is obtained in this manner the A5-173hydroxy2lbenzylidene-pregnadiene in colorless small needles which melt at 184l88 C. EalD24=99 (0:1.023 in chloroform).

For dehydrogenation 9.72 parts of the free hydroxy compound are treated with 1600 parts by volume of toluene and 200 parts by volume of cyclohexanone and the solution dehydrated by distilling ou toluene. Then 5 parts of aluminum isopropylate are added and the :whole boiled for 30 minutes. The cooled mixture is subjected to the addition of 600 parts by volume of molar Rochelle salt solution and treated with steam. The separated ketone is, after cooling, taken up in methylene chloride, Washed with water and the dried. solution evaporatred. The AMV-3- keto 2l benzylidene-pregnadiene crystallizes from ether in colorless prisms of double melting point 179-131 C. and 194-198 C. [alD24=-|-37 (0:1.175 in chloroform).

What we claim is:

1. The All-pregnenes with a substituent selected from the class consisting of a benzylidene, naphthyl-methylidene and furfurylidene group in 2l-position.

2. The Ali-pregnenes with a substituent selected from the class consisting of a benzylidene, naphthyl-methylidene and furfurylidene group in 21-position, which contain in 3- and l2-position a member selected from the group consisting of oxo, hydroxy and lower alkanoic acid ester groups.

3. The ring unsaturated AU-pregnadienes with a substituent selected from the class consisting of a benzylidene, naphthyl-methylidene and furfurylidene group in 21-position, which contain in 3-position a member selected from the group consisting of oxo, hydroxy and lower alkanoic acid ester groups.

4. The A17-3-keto-12-tosyloxy-2l-benzylidenepregnene.

5. The All-Ba-acetoxy-12a-tosy1oxy-21-benzylidene-pregnene.

6. The A1" 3a propionyloxy-l2a-hydroxy-21- furfurylidene-pregnene.

7. The Allf-B-acetoxy-Zl-benzylidene pregnadiene. Y.

8. The Al'l-a-acetoxy-12a-hydroxy-21-benzylidene-pregnene.

KARL MIESCHER. ALBERT WETTSTEIN. JULIUS SCHMIDLIN.

N o references cited. 

1. THE $17-PREGNENES WITH A SUBSTITUENT SELECTED FROM THE CLASS CONSISTING OF A BENZYLIDENE NAPHTHYL-METHYLIDENE AND FURFURYLIDENE GROUP IN 21-POSITION. 